This invention broadly relates to heterocyclic carbon compounds having drug and bio-affecting properties. More particularly, the invention concerns novel purine derivatives which have non-adrenergic smooth muscle relaxant properties making them particularly valuable in overcoming acute bronchospasm and as adjuncts in symptomatic management of chronic, obstructive pulmonary diseases (e.g. asthma, bronchitis, emphysema). It is also concerned with therapeutic methods and compositions employing one or more of the instant compounds as active ingredients.
Regarding types of non-adrenergic bronchodilators, the theophylline group of xanthine derivatives are particular prominent. For instance, aminophylline, the ethylenediamine salt of theophylline, is an effective bronchodilator which may be administered parenterally, orally, or rectally and is useful in patients where direct relaxation of bronchial muscle is desired. Notwithstanding widespread use, the xanthine class of non-adrenergic bronchodilators have major disadvantages with respect to gastric irritation, cardiovascular and central nervous system side effects. Thus, there is a need for new and effective bronchodilators with increased potency and/or fewer or reduced untoward effects. Representative compounds of the instant invention have been shown by standard pharmacological tests to have superior bronchodilating activity relative to aminophylline with reduced cardiovascular and central nervous system side effects.
The basic purine nucleus contains a six-membered pyrimidine ring fused to the five-membered imidazole ring as shown in the following plane formula with the numbering system used herein noted. ##STR1## Various types of purine derivatives are known in which the parent substance purine is substituted at one or more of positions 2, 6 and 9. The following references illustrate such compounds.
1. R. K. Robins, et al., J. Am. Chem. Soc., 83, 2574 (1961) describe synthesis of the compound ##STR2## as a potential antitumor agent from 6-chloro-9-(tetrahydro-2-pyranyl)-purine.
2. U.S. Pat. No. 3,228,937 (Adcock) discloses the compound 6-benzylamino-9-tetrahydropyran-2-yl-9H-purine ##STR3## as a wilting and decay inhibitor for leafy, green plants.
3. R. Marumoto, et al., Chem. Pharm. Bull., 23(4), 759-774 (1975) describes inter alia compounds of the formula ##STR4## wherein R is (lower)alkyl. The compounds are said to have coronary vasodilating activity.
4. H. J. Schaeffer, et al., J. Am. Chem. Soc., 81, 197-201 (1959) describes synthesis of compound having the formula ##STR5## wherein R is cyclohexyl or 2-cyclohexenyl as potential anticancer agents.
5. U.S. Pat. No. 3,917,837 (Lin, et al.) discloses the use of the compound ##STR6## as an anti-inflammatory agent.
6. U.S. Pat. No. 3,862,189 (Schwender) concerns compounds of the formula ##STR7## wherein, inter alia, R.sub.1 is amino, alkylamino, aralkylamino, etc.; and R.sub.2 is phenylalkyl, substituted phenylalkyl, tetrahydroquinoylalkyl, etc. useful as antianginal or bronchodilator agents.
7. U.S. Pat. No. 3,930,005 (Wojnar, et al.) discloses compounds of the formula ##STR8## wherein R.sub.2 and R.sub.3 may be inter alia hydrogen and R.sub.1 may be inter alia (lower)alkoxy as possessing anti-inflammatory activity.